The primary objective of this research is to determine if carbon monoxide has an inhibitory effect on drug metabolism by the lung. An isolated perfused rabbit lung system will be employed since it allows for direct exposure of this organ to carbon monoxide via the trachea, the usual route of entry. Both the parent compounds being studied and their metabolites can be analyzed in perfusate samples. The model compounds to be studied will include those that in vitro would be expected to be affected, i.e., mixed function oxygenase reactions dependent upon cytochrome P-450. These pathways include the N-demethylation of aminopyrine and the hydroxylation of aniline. Because of its direct activation and necrotizing action in the lung, the binding of 4-ipomeanol will also be determined. Non-P-450 dependent activities, the conjugation of phenol and p-nitrophenol and the metabolism of ethanol, will be examined for comparative purposes. By varying the concentration of carbon monoxide to which the lungs are exposed, it will be possible to determine both a minimal effective level and a no effect level. Secondarily, the influence of hemoglobin can be evaluated by comparing the results of perfusion with an artificial perfusate with the perfusion of whole blood. To determine if any effects seen might be due to the hypoxia resulting from carbon monoxide exposure, especially in the blood perfusion studies, parallel experiments will be carried out using hypoxic atmospheres generated by varying the concentration of oxygen. The results of these studies should be useful in evaluating if carbon monoxide exerts any toxic effect on the lungs in terms of capacity for metabolizing drugs or other xenobiotics and, if so, at what level of exposure such influences might be expected to be found. This research should also provide evidence dealing with the detrimental effects of carbon monoxide exposure outside the well-established toxicity associated with carboxyhemoglobin.